The question of what causes MND brings to mind the concept of “known knowns, known unknowns, and unknown unknowns”. Though often associated with the former United States Secretary of Defence Donald Rumsfeld, the idea has been around a lot longer. In terms of MND, and what causes it, the concept highlights the critical role scientific research plays.

MND is in some ways like a bushfire. Once it gets going, it is very difficult to stop. But if we can stamp on the sparks and embers early on we can stop it from getting out of control. When it comes to MND, we need to work out what these embers and sparks are: we need to know what causes MND. If we know what the cause is and what is likely to go wrong, then we can develop treatments to prevent or repair these the defects. It may also help to diagnose the disease more quickly, and to measure the effects of treatments.

Known knowns

With MND there are very few “known knowns” when we look at the causes. The only confirmed causes for MND are mutations in the genes that have been identified, SOD1, c9ORF72 and FUS. And we have seen recently that gene therapies that target SOD1 and FUS have shown good efficacy in slowing or even stopping disease progression.

Known unknowns

The list of “known unknowns” is much longer. These “known unknowns” are the possible causes of MND that are not yet established. The list includes head trauma, vigorous physical activity, exposure to toxic chemicals, smoking and blue-green algae. The hard evidence supporting any of these potential causes is limited. However there is a large amount of information, particularly online, that claims to provide solid evidence to demonstrate their causative roles in MND.

So what do we know?

A very clever mathematical analysis by Ammar Al-Chalabi’s group in London has shown there are 6 steps required to develop MND. The analysis is based on techniques used in cancer. It has been replicated in Australia by Steve Vucic and Matthew Kiernan so we know it is relevant here. Up to 4 of these steps can be contributed by genetic mutations, but 80-90% patients don’t have those mutations. This tells us there is no single cause. In parallel to many cancers, you need multiple “hits”. But, this does not tell us what those “hits” or causes are. So how do we find that out?

Blue-green algae – a case study

As we said previously, many possible causes of MND have been suggested. Many of these theories are based on sound concepts and clever thinking. An example of this is the theory that exposure to blue-green algae¹ causes MND. This theory came about due to a high incidence of an MND-like disease, ALS/ Parkinson’s dementia like-complex (ALS/PDC), in Guam’s Indigenous population, the Chamorros. The Chamorros diet includes cycad seeds and fruit bats, which have high levels of the BMAA toxin.

Higher incidences of MND have been reported in areas with higher than normal levels of blue-green algae. Like cycad seeds and fruit bats, blue-green algae has high levels of BMAA. Hence the hypothesis that blue-green algae causes MND. However, the areas with high levels of blue-green algae are often areas with intense agricultural activity. The Riverina in NSW is a prime example of this. In agricultural areas, other factors come into play, such as a high level of manual work and exposure to chemicals such as fertiliser and pesticides. Proving BMAA is the causative factor means a lot of other factors must be ruled out.

Correlation is not causation: the role of evidence

You need more than a clever idea and a few (possibly coincidental) correlating circumstances to demonstrate a causative effect. This is especially challenging in MND due to the low numbers of patients and the likely variety in contributing factors. It takes a long time to gather enough information associated with a potential cause to be able to make a firm statement as to whether it causes MND. We need hard statistical evidence to prove the role of a causative factor. Unfortunately, sensationalist reporting and misinterpretation of the available data can lead to misinformation (this has been discussed more in-depth in a previous blog piece²). 

Misinformation around causes can be just as damaging as that around treatments. So, how can we gather the evidence we need to find the true causes of MND, and prevent or minimise misinformation?

The importance of research design

Well-designed research studies are the only way to accumulate sufficient data to provide true insights into the causes of MND. These studies need to have clearly-defined objectives with specific variables being tested. Studies must also be sufficiently “powered” i.e. be large enough so statistics can be applied to the data to enable any outcomes to be demonstrably true.

One example might be whether military service contributes to developing MND. The simplest approach is just to see if the incidence of MND in veterans is greater than in the wider population. However, other factors must be considered. These include the gender balance of the military vs the wider population, the incidence of smoking, the relative ages. Apples must be compared with apples and potentially confounding factors considered and if possible removed.

Data, data, data

Two key pillars are absolutely critical to understanding what causes MND: biological research, and data.

We need great researchers to be able to test at the biological level how the factors identified from the data drive disease. In Australia we are extremely well set up for the lab-based studies with our well-supported world-class researchers.

What underpins this research is population level data. The data enables researchers to see where MND is occurring, and what the characteristics are of those developing the disease.

To collect the data, we have now established a strong framework with the MiNDAUS Registry and SALSA database collecting clinical and genetic data on MND patients in Australia. However not every patient is currently captured and longer-term financial support for these critical initiatives needs to be established. MND Australia is currently working with other partners in the MND community to ensure we have a comprehensive and sustainable data collection framework in place that captures every MND patient in Australia.

By Dr Gethin Thomas, Executive Director of Research, and Melissa Fagan, Information Resource Development Manager 

References

1. www.ncbi.nlm.nih.gov/pmc/articles/PMC3194113/?tool=pmcentrez&rendertype=abstract